Safety Lessons for YAP/TAZ–TEAD Inhibition: From Mechanism to Translation

CT006 [2023]), kidney-related adverse effects have recently emerged, characterized nonclinically or clinically by proteinuria, albuminuria, podocyte injury, and tubular degeneration. Evidence from genetics, organoids, and human-induced pluripotent stem cell (hiPSC) models indicates that YAP/TAZ-TEAD activity is integral to podocyte and tubular homeostasis, providing a mechanistic explanation for the kidney susceptibility. In this review, we summarize nonclinical and early clinical safety observations with pan-TEAD inhibitors, highlight organs most at risk, and discuss approaches that could be taken to optimize the therapeutic index of TEAD inhibitors, like paralog selectivity, adaptive/intermittent dosing, and monitoring of translational biomarkers with pharmacodynamic readouts. Integrating the mechanistic insights and safety lessons learned so far from targeting this pathway could guide safer clinical development of TEAD-directed therapies in the future.